PROJECT SUMMARY Recent epidemiologic and clinical studies have affirmed the coexistence of erection and voiding disorders, such as erectile dysfunction and lower urinary tract symptoms, which indicates a true disease syndrome. The significance of this coexisting condition relates to its prevalence (as much as 20% of men) and impact (having quality-of-life ramifications and associations with other health co-morbidities). Coexisting erection and voiding disorders are also observed in sickle cell disease, which may offer a special paradigm to study and establish the science for their coexistence. Delineation of this link on scientific grounds would serve to develop needful, mechanism-specific interventions for coexistent erection and voiding disorders. In the sickle cell disease population, mounting scientific evidence has pointed to chronically defective function of nitric oxide, a major chemical regulator of biological processes in the body, as a fundamental factor for much of its various disease- related complications. Sickle cell disease offers a potentially informative paradigm by which to study and define dysregulated nitric oxide function as a likely determinant of concomitant erection and voiding disorders. Therefore, this research proposal is designed to investigate dysregulatory mechanisms of nitric oxide signaling of the lower genitourinary tract applying experimental biologic systems of nitric oxide signaling dysregulation and nitric oxide-based restorative interventions. The experimental plan will involve a combination of molecular, pharmacologic and physiologic techniques, using a genetically engineered sickle cell disease mouse model (which has been used advantageously for the study of erection disorders). Specific aims are: (1) to evaluate lower urinary tract dysfunction in the sickle cell disease mouse as a possible progressive bladder failure phenotype; (2) to evaluate derangements of nitric oxide signaling in the lower genitourinary tract of the sickle cell disease mouse; (3) to evaluate whether transnitrosylation (a major protein interaction regulatory mechanism) of constitutive nitric oxide synthase regulates lower genitourinary tract function; and (4) to evaluate whether nitric oxide treatment attenuates lower genitourinary tract dysfunction.